The early stages of atherosclerosis are characterized by macrophage invasion of the intimal space and proliferation of smooth muscle cells (SMCs). In this study, we characterize the timing and location of each of these processes. Dividing cells of the developing lesions were labeled with [3H]thymidine at different times during lesion progression. Comparable stages of lesion development were analyzed, with the only variable being the length of time between labeling and necropsy. In this way, the mechanism by which lesion composition changes could be inferred from changes in the distribution of label over time. When cells were labeled just before necropsy, serial sections showed monocyte influx predominantly occurring at lesion edges and resulting in a labeling index of 27%. Near the lesion edge, medial SMCs were not stimulated to proliferate. In contrast, in more central areas of the lesion, monocyte influx and intimal SMC proliferation were minimal. Medial SMC proliferation in central regions, however, was high, with a labeling index of 20% in the upper media. Over time, proliferating medial SMCs migrated into the intimal lesion but did not migrate laterally to any great extent. This migration pattern maintained precise subdomains during lesion development, with each domain representing a different stage of lesion development. The edge of lesions thus represents very early events, central regions indicate later events, and intermediate regions provide information about stages between these extremes.